PROJECT SUMMARY Our laboratory has demonstrated an essential role for sensory nerves in the ossification of the developing mouse limb. Here, we validated and leveraged several reporter systems to visualize and perturb sensory innervation in mineralized tissues of the long bone. However, unlike the appendicular skeleton, the role of the peripheral nervous system (PNS) in the postnatal craniofacial skeleton remains largely unexplored. In our preliminary work, we demonstrate that the neurotrophin NGF (nerve growth factor) has extensive and specific domains of expression within suture mesenchyme of patent cranial sutures, and that this corresponds with dense innervation of TrkA+ (tropomyosin receptor kinase A) sensory nerves. These observations, and other studies described below, provide the first evidence for the requirement of TrkA sensory nerves in craniofacial skeletal ossification and repair. The studies outlined in this proposal will explore the mechanisms through which sensory nerves function to regulate osteogenesis. Our approach will test the hypothesis that nerve growth factor (NGF) produced in the injured calvarial bone activates TrkA sensory neurons to promote their survival and guide their axons to areas of osteogenesis, vasculogenesis, and bone repair. This hypothesis will be tested in the setting of an established model of experimental bone injury, using a healing circular bone defect adjacent to the patent sagittal suture. We believe that our project will yield new insights into the role of sensory nerves in healthy humans and will ultimately inform on the neuropathological manifestations associated with certain bone disorders.